In this exploratory project, we propose to test a new hypothesis that deficiencies in the brain's reserves of energy make it vulnerable to stress and constitute a risk factor in the development of depression. Normal brain function is dependent on the expenditure of large amounts of energy (up to 20 percent of all energy needs in the human) and most of this energy is consumed in maintaining electrical potentials and ionic gradients across neuronal cell membranes. Exposure to stressful conditions induces greatly increased energy consumption in specific areas of the brain, and the ability of a neuron to respond normally to stressors and to survive the excited state that stressors produce is dependent on surrounding glial cells providing energy in the form of glucose and glucose metabolites. The glial cell's ability to provide energy sources to neurons is not only dependent on the transport of glucose from the blood but also on the mobilization of its own glycogen energy reserves. In response to excitatory neurotransmitters, glial cells break down glycogen into glucose and lactic acid and export them to neurons. We will determine if depression results when the brain is exposed to stressful conditions of sufficient intensity and duration as to deplete the glial glycogen reserve in specific regions of the brain. Depleted glial cells would then be unable to provide nearby neurons with sufficient glucose and lactic acid, and neuroprotective responses to the energy deficit would reduce local neural activity and cause symptoms of depression. We present new data using a well-established animal model of depression that support the glycogen hypothesis. These data indicate that stressful conditions sufficient to cause behavioral depression not only deplete cerebral glycogen but also cause a profound metabolic deficit. In the planned experiments, we shall (a) examine the effects of depression-inducing stressors on levels of glycogen in different brain areas, (b) monitor brain glucose and lactic acid release during exposure to the stressor and during the development and recovery from behavioral depression, and (c) examine the neurochemical and behavioral effects of manipulating brain glycogen levels. Results will provide entirely new insights into the mechanisms of stress induced depression and should suggest new approaches to the treatment and prevention of this devastating disease.